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Wednesday, June 29, 2022

Colorectal cancer remission with immune checkpoint inhibitor drugs

Dr. Gabe Mirkin

Fourteen patients with “mismatched-repair” colorectal cancers were given a drug called dostarlimab every three weeks for six months, and follow-up after two years found that none of the patients had any remaining evidence of cancer (NEJM, June 5, 2022). This is an incredible result because all patients had complete remission and none suffered serious reactions to the drug. The conventional treatments for colorectal cancer (radiation, chemotherapy and surgery) often cause permanent infertility, bowel and bladder damage, and loss of sexual function.

“Mismatched-repair” means that the cancer is caused genetically by lack of enzymes to get rid of abnormal DNA that increases cancer risk (J Gastrointest Oncol, 2013 Dec; 4(4): 397–408). It occurs in four percent of cancers and 15 percent of colorectal cancers (Cancer Res 1994;54:1645-8). Drugs to treat “mismatched-repair” cancers are based on the work on immune checkpoint inhibitors by Jim Allison, winner of the 2018 Nobel Prize.

What is an Immune Checkpoint Inhibitor?
Everyone makes millions of cancer cells every day, but your immune system can tell the difference between normal cells and those that are cancerous, and the cancer cells are destroyed. Your immune system has two types of killer lymphocyte cells that destroy cancer cells:
• T cells that come from your thymus gland
• B cells that come from your bone marrow
T cells recognize that cancer cells are different from normal cells, so T cells tell B cells that cancer cells are different from normal cells and are harmful; and then B cells attack and kill the cancer cells.

Before Jim Allison came along, scientists knew that the T cells recognized cancer cells and passed on this information to the B cells, so for many years, scientists spent time trying to increase the stimulator made by the T cell to teach the B cell to kill the cancer, but this never worked. Then Allison showed that these scientists were wrong. Instead of stimulating the T cell to make more chemicals that stimulate the B cell, Allison showed that T cells also produce an “inhibitor” that slows down the B cell so that it doesn’t become stimulated so much that it attacks normal cells in the body as well as invading germs and cancer cells, which can be fatal.

Allison had to fend off a lot of skeptical scientists who laughed at him and considered him an upstart, but he was correct. This treatment for cancer includes inhibiting the inhibitor that the T cell sends to the B cell. By inhibiting the inhibitor produced by the T cell, the T cell could produce B cell stimulators without inhibition and they could attack and kill the cancer cells. These new cancer treatment drugs that block T cell inhibitors are called checkpoint inhibitors, and they are curing some patients with cancers that were formerly considered to be hopeless (Jimmy Carter’s treatment of metastasized melanoma skin cancer was an early and widely publicized success).

Most Cases of Colorectal Cancer Are Not Genetic
Cancer is caused by inherited genetic mistakes (such as the “mismatched-repair” cases in this study), or by harmful environmental and lifestyle factors. In colorectal cancers, about 15 percent are believed to be caused primarily by genetic factors, and 85 percent are associated with environmental factors such as:
• Drinking alcoholic beverages (EClinicalMedicine, July 1, 2022)
• Eating processed or unprocessed mammal meats (JAMA Netw Open, 2022;5(2):e220145)
• Drinking sugar-sweetened beverage and eating sugar-added foods (American J Clinical Nutrition, June 2022;115(6):1481–1489)
• Not eating lots of fruits and vegetables (JAMA Netw Open, 2021;4(2):e2037341)
• Not exercising (International Journal of Cancer, April 7, 2022)
• Smoking and second-hand smoke (Gut, April 6, 2022)
• Being overweight (JAMA Oncol, 2022;8(5):730-737)
• Various chemicals and radiation sources in the environment

My Recommendations
This is a very important study because it suggests that a certain type of colon cancer with a known genetic cause is highly curable with a drug called dostarlimab. If future larger studies provide the same results, every case of colorectal cancer will be checked to see if it is “mismatched-repair,” and if it is, treatment will be with checkpoint inhibitor drugs. The study was done in Memorial Sloan Kettering Cancer Center. Dostarlimab is sold under the brand name Jemparli and is made by GlaxoSmithKline. It is likely to be very expensive ($11,000 per dose in this study.)

Dr. Gabe Mirkin is a Villager. Learn more at www.drmirkin.com

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